The susceptibility of insulin dependent diabetics to hypoglycemia can in part be attributed to their defective counterregulatory hormonal response, which fails to stimulate adequate glucose production. Endurance training has long been known to induce resistance to exercise induced hypoglycemia, despite suppressed counterregulatory hormone responses. Our long term goal is to elucidate mechanism(s) by which endurance training induces improved hepatic responsiveness to elevations in counterregulatory hormones and precursor supply. Thus, facilitating the development of interventions aimed at enhancing resistance to hypoglycemia. For the endurance trained rat, our lab and others have demonstrated that this resistance to hypoglycemia is achieved through elevated glucose production, via enhanced gluconeogenic responsiveness. Utilizing the in situ perfused liver preparation, we have demonstrated training enhanced hepatic gluconeogenesis in response to elevated deliveries of both lactate and alanine. More recently, utilizing a pseudo physiological perfusate we have demonstrated a three-fold greater gluconeogenic response to elevations in glucagon in the liver of endurance trained animals (see Preliminary Results). For the current proposal our general hypothesis is that endurance training enhances hepatic gluconeogenic sensitivity/responsiveness to glucagon through specific adaptations in cAMP signal transduction. Experiments are proposed with the following specific aims: l) to elucidate the impact of training on the true hormone/metabolite milieu perfusing livers in vivo, 2) to ascertain the impact of endurance training upon glucagon sensitivity and maximal responsiveness for hepatic gluconeogenesis under physiological conditions, and 3) to ascertain the site(s) of adaptation responsible for the enhanced sensitivity/ responsiveness subsequent to endurance training.